tbuckley/cabot-search huggingface dataset:
Synergistic activation of AMPK by AdipoR1/2 agonist and inhibitor of EDPs–EBP interaction recover NAFLD through enhancing mitochondrial function in mice
Authors: Nazi Song, Hongjiao Xu, Shuohan Wu, Suijia Luo, Jingyao Xu, Qian Zhao, Rui Wang, Xianxing Jiang
Journal: Acta Pharmaceutica Sinica B (2022)

Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH), is a common hepatic manifestation of metabolic syndrome. However, there are no effective therapy to treat this devastating disease. Accumulating evidence suggests that the generation of elastin-derived peptides (EDPs) and the inhibition of adiponectin receptors (AdipoR)1/2 plays essential roles in hepatic lipid metabolism and liver fibrosis. We recently reported that the AdipoR1/2 dual agonist JT003 significantly degraded the extracellular matrix (ECM) and ameliorated liver fibrosis. However, the degradation of the ECM lead to the generation of EDPs, which could further alter liver homeostasis negatively. Thus, in this study, we successfully combined AdipoR1/2 agonist JT003 with V14, which acted as an inhibitor of EDPs-EBP interaction to overcome the defect of ECM degradation. We found that combination of JT003 and V14 possessed excellent synergistic benefits on ameliorating NASH and liver fibrosis than either alone since they compensate the shortage of each other. These effects are induced by the enhancement of the mitochondrial antioxidant capacity, mitophagy, and mitochondrial biogenesis via AMPK pathway. Furthermore, specific suppression of AMPK could block the effects of the combination of JT003 and V14 on reduced oxidative stress, increased mitophagy and mitochondrial biogenesis. These positive results suggested that this administration of combination of AdipoR1/2 dual agonist and inhibitor of EDPs-EBP interaction can be recommended alternatively for an effective and promising therapeutic strategy for the treatment of NAFLD and NASH related fibrosis.
Brigatinib versus Crizotinib in ALK Inhibitor–Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial
Authors: D Ross Camidge, Hye-Ryun Kim, Myung-Ju Ahn, James Yang, Ji-Youn Han, Maximilian Hochmair, Ki Lee, Angelo Delmonte, Maria Rosario, Garcia Campelo, Dong-Wan Kim, Frank Griesinger, Enriqueta Felip, Raffaele Califano, Alexander Spira, Scott Gettinger, Marcello Tiseo, Huamao Lin, Yuyin Liu, Florin Vranceanu, Huifeng Niu, Pingkuan Zhang, Sanjay Popat, D Camidge
Journal: Journal of Thoracic Oncology (2022)
Cartilage Acidic Protein 1 in Plasma Associates With Prevalent Osteoarthritis and Predicts Future Risk as Well as Progression to Joint Replacements: Results From the <scp>UK</scp> Biobank Resource
Authors: Unnur Styrkarsdottir, Sigrun H. Lund, Gudmar Thorleifsson, Saedis Saevarsdottir, Daniel F. Gudbjartsson, Unnur Thorsteinsdottir, Kari Stefansson
Journal: Arthritis & Rheumatology (2022)

Objective The level of cartilage acidic protein 1 (CRTAC1) in plasma was recently discovered to be associated with osteoarthritis (OA) risk and progression to joint replacement in Iceland. This study was undertaken to validate these findings in an independent population. Methods In this study, 1,462 plasma proteins were measured in 54,265 participants from the UK Biobank on the Olink Explore platform. We analyzed the association of plasma proteins with prevalent OA, incident OA, and progression to joint replacement. We assessed the specificity of OA association through comparison of associations with inflammatory joint diseases and with previous joint replacement. Results The CRTAC1 protein showed the strongest association with prevalent knee OA (odds ratio [OR] 1.34 [95% confidence interval (95% CI) 1.27, 1.41]) and was associated with hip OA (OR 1.19 [95% CI 1.11, 1.28]). It predicted incident diagnosis of OA in the knee (hazard ratio [HR] 1.40 [95% CI 1.35, 1.46]) and hip (HR 1.25 [95% CI 1.19, 1.31]), as well as progression to joint replacement (HR 1.20 [95% CI 1.08, 1.33] for the knee and HR 1.22 [95% CI 1.08, 1.38] for the hip), while no association was found with inflammatory joint diseases. Individuals in the highest quintile of risk based on CRTAC1 level, age, sex, and body mass index had a 10‐fold risk of knee or hip OA within 5 years compared to those in the lowest quintile. Adding aggrecan core protein (ACAN) and neurocan core protein (NCAN) to the model improved the prediction of OA but not joint replacement. Furthermore, we replicated the association of CUB domain–containing protein 1 with prior joint replacement. Conclusion Plasma CRTAC1 is a specific biomarker for OA and a predictor of OA risk and progression to joint replacement. Adding ACAN and NCAN protein levels to the CRTAC1 model improved the prediction of OA.
The role of transcription factors in the acquisition of the four latest proposed hallmarks of cancer and corresponding enabling characteristics
Authors: Maria P. Morgan, Ellen Finnegan, Sudipto Das
Journal: Seminars in Cancer Biology (2022)

With the recent description of the molecular and cellular characteristics that enable acquisition of both core and new hallmarks of cancer, the consequences of transcription factor dysregulation in the hallmarks scheme has become increasingly evident. Dysregulation or mutation of transcription factors has long been recognized in the development of cancer where alterations in these key regulatory molecules can result in aberrant gene expression and consequential blockade of normal cellular differentiation. Here, we provide an up-to-date review of involvement of dysregulated transcription factor networks with the most recently reported cancer hallmarks and enabling characteristic properties. We present some illustrative examples of the impact of dysregulated transcription factors, specifically focusing on the characteristics of phenotypic plasticity, non-mutational epigenetic reprogramming, polymorphic microbiomes, and senescence. We also discuss how new insights into transcription factor dysregulation in cancer is contributing to addressing current therapeutic challenges.
The Sequential Application of Baveno VII Criteria and VITRO Score Improves Diagnosis of Clinically Significant Portal Hypertension
Authors: Mathias Jachs, Lukas Hartl, Benedikt Simbrunner, David Bauer, Rafael Paternostro, Bernhard Scheiner, Lorenz Balcar, Georg Semmler, Albert Friedrich Stättermayer, Matthias Pinter, Peter Quehenberger, Michael Trauner, Thomas Reiberger, Mattias Mandorfer
Journal: Clinical Gastroenterology and Hepatology (2022)

Baveno VII proposed liver stiffness measurement (LSM)/platelet count (PLT)-based criteria ('ruled out,' LSM ≤15 kPa plus PLT ≥150 G/L; 'ruled in': LSM ≥25 kPa) for clinically significant portal hypertension (CSPH) in compensated advanced chronic liver disease (cACLD). However, a substantial proportion of patients remains 'unclassified.'Patients with evidence of cACLD (LSM ≥10 kPa) undergoing hepatic venous pressure gradient (HVPG) measurement at the Vienna General Hospital 2004 to 2021 (derivation [2004-2016], n = 221; validation [2017-2021], n = 81) were included. The performance of noninvasive tests (NITs) including von Willebrand factor antigen to PLT ratio (VITRO) for the detection of CSPH (HVPG ≥10 mmHg) were evaluated.Overall, viral hepatitis was the predominant (50.7%) etiology, followed by alcoholic liver disease (15.2%) and nonalcoholic steatohepatitis (13.2%); CSPH prevalence was 62.3%. In the derivation cohort, 45.7% were 'unclassified' according to Baveno VII criteria; in this group, VITRO showed an excellent diagnostic performance for the detection of CSPH (area under the receiver operating curve, 0.909; 95% confidence interval, 0.823-0.965). VITRO ≤1.5 and ≥2.5 ruled out (sensitivity, 97.7%; negative predictive value, 97.5%) and ruled in (specificity, 94.7%; positive predictive value, 91.2%), respectively, CSPH in patients who were 'unclassifiable' by Baveno VII criteria. The application of a sequential Baveno VII-VITRO algorithm reallocated 73% and 70% of 'unclassified' patients to the 'ruled in' and 'ruled out' group, respectively, while maintaining high sensitivity and negative predictive value and specificity and positive predictive value in the derivation and validation cohort, respectively. No patient allocated to the 'CSPH ruled out' group by the Baveno VII-VITRO algorithm developed decompensation within 5 years, whereas 5-year decompensation rates were negligible (4%) and substantial (23.9%) among 'unclassified' and 'CSPH ruled in' patients, respectively.The sequential application of VITRO in patients with cACLD who were 'unclassifiable' with regard to CSPH by Baveno VII criteria substantially decreased the number of 'unclassifiable' patients to <15% and refined prognostication.
Ectopic clotting factor VIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma
Authors: Audrey Kapelanski-Lamoureux, Zhouji Chen, Zu-Hua Gao, Ruishu Deng, Anthoula Lazaris, Cynthia Lebeaupin, Lisa Giles, Jyoti Malhotra, Jing Yong, Chenhui Zou, Ype P. de Jong, Peter Metrakos, Roland W. Herzog, Randal J. Kaufman
Journal: Molecular Therapy (2022)

Hemophilia A gene therapy targets hepatocytes to express B domain deleted (BDD) clotting factor VIII (FVIII) to permit viral encapsidation. Since BDD is prone to misfolding in the endoplasmic reticulum (ER) and ER protein misfolding in hepatocytes followed by high-fat diet (HFD) can cause hepatocellular carcinoma (HCC), we studied how FVIII misfolding impacts HCC development using hepatocyte DNA delivery to express three proteins from the same parental vector: (1) well-folded cytosolic dihydrofolate reductase (DHFR); (2) BDD-FVIII, which is prone to misfolding in the ER; and (3) N6-FVIII, which folds more efficiently than BDD-FVIII. One week after DNA delivery, when FVIII expression was undetectable, mice were fed HFD for 65 weeks. Remarkably, all mice that received BDD-FVIII vector developed liver tumors, whereas only 58% of mice that received N6 and no mice that received DHFR vector developed liver tumors, suggesting that the degree of protein misfolding in the ER increases predisposition to HCC in the context of an HFD and in the absence of viral transduction. Our findings raise concerns of ectopic BDD-FVIII expression in hepatocytes in the clinic, which poses risks independent of viral vector integration. Limited expression per hepatocyte and/or use of proteins that avoid misfolding may enhance safety.
Pegylated Liposomal Doxorubicin Combined with Ifosfamide for Treating Advanced or Metastatic Soft-tissue Sarcoma: A Prospective, Single-arm Phase II Study
Authors: Xin Liu, Shiyu Jiang, Huijie Wang, Xianghua Wu, Wangjun Yan, Yong Chen, Yu Xu, Chunmeng Wang, Weiqiang Yao, Jian Wang, Lin Yu, Jiashun Miao, Hao Chen, Jing Xia, Mengli Huang, Xiaowei Zhang, Zhiguo Luo
Journal: Clinical Cancer Research (2022)

Abstract Purpose: This prospective single-arm phase II clinical trial aimed to evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) combined with ifosfamide (IFO) as the first-line treatment for patients with advanced or metastatic soft-tissue sarcoma (STS). Patients and Methods: Patients received PLD (30 mg/m2; day 1) in combination with IFO (1.8 g/m2; days 1–5) every 21 days until disease progression, unacceptable toxicities, patient death, or for up to six cycles. The primary endpoint was progression-free survival (PFS; NCT03268772). Results: Overall, 69 patients with chemotherapy-naïve advanced or metastatic STS were enrolled between May 2015 and November 2019. At a median follow-up of 47.2 months, the median PFS and overall survival (OS) were found to be 7.3 [95% confidence interval (CI): 5.7–8.9] and 20.6 (95% CI: 16.3–25.0) months, respectively. The response and disease control rates were 26.1% and 81.2%, respectively. Adverse events were manageable, and no grade 3–4 cardiotoxicities were observed. There was no significant change in left ventricular ejection fraction values between baseline and after treatment (P = 0.669). Exploratory biomarker analysis suggested NF1 single-nucleotide variant was associated with poor OS (P &amp;lt; 0.0001) and PFS (P = 0.044). In addition, 2 patients with BRCA2 loss progressed in the initial 2 months and died within 10 months. Improved OS was observed in homologous recombination deficiency (HRD)-negative patients compared with their HRD-positive counterparts (P = 0.0056). Conclusions: Combination therapy comprising PLD and IFO is an effective and well-tolerated first-line treatment for patients with advanced or metastatic STS.
Author Correction: Ectopic JAK–STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance
Authors: Su Deng, Choushi Wang, Yunguan Wang, Yaru Xu, Xiaoling Li, Nickolas A. Johnson, Atreyi Mukherji, U-Ging Lo, Lingfan Xu, Julisa Gonzalez, Lauren A. Metang, Jianfeng Ye, Carla Rodriguez Tirado, Kathia Rodarte, Yinglu Zhou, Zhiqun Xie, Carlos Arana, Valli Annamalai, Xihui Liu, Donald J. Vander Griend, Douglas Strand, Jer-Tsong Hsieh, Bo Li, Ganesh Raj, Tao Wang, Ping Mu
Journal: Nature Cancer (2022)
WONCA Europe position statement on the redefinition of fatty liver disease
Authors: Shlomo Vinker, Thomas Frese, Eva Hummers, Zalika Klemenc Ketiš, Adam Windak, Ferdinando Petrazzuoli, Jose-Miguel Bueno-Ortiz, Radost Asenova, Aaron Poppleton, Nahum Méndez-Sánchez
Journal: The Lancet. Gastroenterology & hepatology (2022)
The burden of bacterial antimicrobial resistance in the WHO European region in 2019: a cross-country systematic analysis
Authors: Tomislav Mestrovic, Gisela Robles Aguilar, Lucien R Swetschinski, Kevin S Ikuta, Authia P Gray, Nicole Davis Weaver, Chieh Han, Eve E Wool, Anna Gershberg Hayoon, Simon I Hay, Christiane Dolecek, Benn Sartorius, Christopher J L Murray, Isaac Yeboah Addo, Bright Opoku Ahinkorah, Ayman Ahmed, Mamoon A Aldeyab, Kasim Allel, Robert Ancuceanu, Anayochukwu Edward Anyasodor, Marcel Ausloos, Fabio Barra, Akshaya Srikanth Bhagavathula, Dinesh Bhandari, Sonu Bhaskar, Natália Cruz-Martins, Anna Dastiridou, Klara Dokova, Eleonora Dubljanin, Oyewole Christopher Durojaiye, Adeniyi Francis Fagbamigbe, Simone Ferrero, Peter Andras Gaal, Veer Bala Gupta, Vijai Kumar Gupta, Vivek Kumar Gupta, Claudiu Herteliu, Salman Hussain, Irena M Ilic, Milena D Ilic, Elham Jamshidi, Tamas Joo, André Karch, Adnan Kisa, Sezer Kisa, Tomislav Kostyanev, Hmwe Hmwe Kyu, Judit Lám, Graciliana Lopes, Alexander G Mathioudakis, Alexios-Fotios A Mentis, Irmina Maria Michalek, Mohammad Ali Moni, Catrin E Moore, Francesk Mulita, Ionut Negoi, Ruxandra Irina Negoi, Tamás Palicz, Adrian Pana, João Perdigão, Ionela-Roxana Petcu, Navid Rabiee, David Laith Rawaf, Salman Rawaf, Murad Ziyaudinovich Shakhmardanov, Aziz Sheikh, Luís Manuel Lopes Rodrigues Silva, Valentin Yurievich Skryabin, Anna Aleksandrovna Skryabina, Bogdan Socea, Andy Stergachis, Temenuga Zhekova Stoeva, Chandra Datta Sumi, Arulmani Thiyagarajan, Marcos Roberto Tovani-Palone, Metin Yesiltepe, Sojib Bin Zaman, Mohsen Naghavi
Journal: The Lancet Public Health (2022)
Intrapericardial Exosome Therapy Dampens Cardiac Injury via Activating Foxo3
Authors: Dashuai Zhu, Shuo Liu, Ke Huang, Zhenzhen Wang, Shiqi Hu, Junlang Li, Zhenhua Li, Ke Cheng
Journal: Circulation Research (2022)

Mesenchymal stem cell (MSC)-derived exosomes are well recognized immunomodulating agents for cardiac repair, while the detailed mechanisms remain elusive. The Pericardial drainage pathway provides the heart with immunosurveillance and establishes a simplified model for studying the mechanisms underlying the immunomodulating effects of therapeutic exosomes.
Cancer therapy by antibody-targeted Cerenkov light and metabolism-selective photosensitization
Authors: Chihoon Jo, Heesu Ahn, Ji Hwan Kim, Yong Jin Lee, Jung Young Kim, Kyo Chul Lee, Chi Soo Kang, Sehoon Kim
Journal: Journal of Controlled Release (2022)

Photodynamic therapy (PDT) is an effective cancer treatment option, but it suffers from penetration limit of light, making it available only for superficial and endoscopically accessible cancers. Recently, there have been reports that Cerenkov luminescence originated from radioisotopes can be utilized as an excitation source for PDT without external light illumination. Here, cancer-selective agents, i.e., (1) clinically available 5-aminolevulinic acid (5-ALA), which promotes cancer metabolism-specific accumulation of protoporphyrin IX (PpIX), and (2) 64Cu-DOTA-trastuzumab, which has HER2-expressing cancer selective uptake, are separately applied as a photosensitizer and an in situ radiator, respectively, to potentiate tumor-specific Cerenkov luminescence energy transfer (CLET) from 64Cu to PpIX for high-precision PDT of cancer. It is shown that the combinational administration and tumor colocalization of 5-ALA and 64Cu-DOTA-trastuzumab exert significant in vitro cytotoxicity (cell viability <9%) as well as in vivo antitumor effects (tumor volume ratio of 0.50 on 14 days post-injection) on HER2-expressing breast and gastric cancer models. This study proves that high-precision treatment regimen using dual-targeted CLET-based PDT is feasible for HER2-expressing cancers. Furthermore, the results offer great potential for clinical translation to the dual-targeted CLET-based PDT because the treatment regimen uses components, 5-ALA and 64Cu-DOTA-trastuzumab, which are already in clinical uses.
Safety and Efficacy of Intraventricular Immunovirotherapy with Oncolytic HSV-1 for CNS Cancers
Authors: Kyung-Don Kang, Joshua D. Bernstock, Stacie K. Totsch, Sam E. Gary, Abbey Rocco, Li Nan, Rong Li, Tina Etminan, Xiaosi Han, Elizabeth A. Beierle, Tanja Eisemann, Robert J. Wechsler-Reya, Sejong Bae, Richard Whitley, G. Yancey Gillespie, James M. Markert, Gregory K. Friedman
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Oncolytic virotherapy with herpes simplex virus-1 (HSV) has shown promise for the treatment of pediatric and adult brain tumors; however, completed and ongoing clinical trials have utilized intratumoral/peritumoral oncolytic HSV (oHSV) inoculation due to intraventricular/intrathecal toxicity concerns. Intratumoral delivery requires an invasive neurosurgical procedure, limits repeat injections, and precludes direct targeting of metastatic and leptomeningeal disease. To address these limitations, we determined causes of toxicity from intraventricular oHSV and established methods for mitigating toxicity to treat disseminated brain tumors in mice. Experimental Design: HSV-sensitive CBA/J mice received intraventricular vehicle, inactivated oHSV, or treatment doses (1×107 plaque-forming units) of oHSV, and toxicity was assessed by weight loss and IHC. Protective strategies to reduce oHSV toxicity, including intraventricular low-dose oHSV or interferon inducer polyinosinic-polycytidylic acid (poly I:C) prior to oHSV treatment dose, were evaluated and then utilized to assess intraventricular oHSV treatment of multiple models of disseminated CNS disease. Results: A standard treatment dose of intraventricular oHSV damaged ependymal cells via virus replication and induction of CD8+ T cells, whereas vehicle or inactivated virus resulted in no toxicity. Subsequent doses of intraventricular oHSV caused little additional toxicity. Interferon induction with phosphorylation of eukaryotic initiation factor-2α (eIF2α) via intraventricular pretreatment with low-dose oHSV or poly I:C mitigated ependyma toxicity. This approach enabled the safe delivery of multiple treatment doses of clinically relevant oHSV G207 and prolonged survival in disseminated brain tumor models. Conclusions: Toxicity from intraventricular oHSV can be mitigated, resulting in therapeutic benefit. These data support the clinical translation of intraventricular G207.
Incidence and Survival in Synchronous and Metachronous Liver Metastases From Colorectal Cancer
Authors: Noémi Reboux, Valérie Jooste, Juste Goungounga, Michel Robaszkiewicz, Jean-Baptiste Nousbaum, Anne-Marie Bouvier
Journal: JAMA Network Open (2022)

Importance Although treatment and prognosis of synchronous liver metastases from colorectal cancer are relatively well known, a comparative description of the incidence, epidemiological features, and outcomes of synchronous and metachronous liver metastases is lacking. The difference in prognosis between patients with synchronous and metachronous liver metastases is controversial. Objective To investigate temporal patterns in the incidence and outcomes of synchronous vs metachronous liver metastases from colorectal cancer. Design, Setting, and Participants This population-based cohort study used information from a French regional digestive cancer registry accounting for 1 082 000 inhabitants. A total of 26 813 patients with a diagnosis of incident colorectal adenocarcinoma diagnosed between January 1, 1976, and December 31, 2018, were included. Data were analyzed from February 7 to May 20, 2022. Main Outcomes and Measures Age-standardized incidence was calculated. Univariate and multivariate net survival analyses were performed. Results Of 26 813 patients with colorectal cancer (15 032 men [56.1%]; median [IQR] age, 73 [64-81] years), 4546 (17.0%) presented with synchronous liver metastases. The incidence rate of synchronous liver metastases was 6.9 per 100 000 inhabitants in men and 3.4 per 100 000 inhabitants in women, with no significant variation since 2000. The 5-year cumulative incidence of metachronous liver metastases decreased from 18.6% (95% CI, 14.9%-22.2%) during the 1976 to 1980 period to 10.0% (95% CI, 8.8%-11.2%) during the 2006 to 2011 period. Cancer stage at diagnosis was the strongest risk factor for liver metastases; compared with patients diagnosed with stage II cancer, patients with stage III cancer had a 2-fold increase in risk (subdistribution hazard ratio, 2.42; 95% CI, 2.08-2.82) for up to 5 years. Net survival at 1 year was 41.8% for synchronous liver metastases and 49.9% for metachronous metastases, and net survival at 5 years was 6.2% for synchronous liver metastases and 13.2% for metachronous metastases. Between the first (1976-1980) and last (2011-2016) periods, the adjusted ratio of death after synchronous and metachronous metastases was divided by 2.5 for patients with synchronous status and 3.7 for patients with metachronous status. Conclusions and Relevance In this study, the incidence of colorectal cancer with synchronous liver metastases changed little over time, whereas there was a 2-fold decrease in the probability of developing metachronous liver metastases. Survival improved substantially for patients with metachronous liver metastases, whereas improvement was more modest for those with synchronous metastases. The differences observed in the epidemiological features of synchronous and metachronous liver metastases from colorectal cancer may be useful for the design of future clinical trials.
Trends in the Association Between Diabetes and Cardiovascular Events, 1994-2019
Authors: Calvin Ke, Lorraine L. Lipscombe, Alanna Weisman, Limei Zhou, Peter C. Austin, Baiju R. Shah, Gillian L. Booth
Journal: JAMA (2022)

This study uses administrative health care data from Ontario, Canada, to assess whether changes in diabetes management practices have affected trends in the association between diabetes vs prior cardiovascular disease and risk of cardiovascular events from 1994 to 2019 among adults aged 20 to 84 years.
Targeted Therapy on the Screen: Do We Hit the Target?
Authors: Heidi Lyng, Kjersti Skipar, Tord Hompland
Journal: Clinical Cancer Research (2022)

Summary A phase II trial, investigating whether the antidiabetic drug metformin could reduce hypoxia in cervical cancer, used imaging to preselect patients and test the biological hypothesis behind the drug effect. This trial design would be of importance for the implementation of targeted treatment in the clinic. See related article by Han et al., p. 5263